Immune-Checkpoint-Inhibitors (ICIs) have significantly improved the course of advanced/metastatic melanoma and the concept of ICIs curative potential began to appear. To use statistical approaches to determine whether advanced/metastatic melanoma patients treated with nivolumab alone or in combination with ipilimumab may be considered as functionally cured. Individual patient data were reconstructed from published Kaplan-Meier curves of the anti-PD1 arms of the Checkmate-067. The assumption of functional cure was assessed using three approaches based on a flexible-parametric survival model. Once the hypothesis of functional cure was confirmed, the time to functional cure (TTFC) was determined using an intuitive approach based on flexible survival model. The three complementary approaches were consistent and confirmed the functional cure assumption. The TTFC (the shortest time defined by fewer than 1% of patients progressing or dying) was estimated to be 61 (95%CI,50.7;79.4) and 63 m (95%CI,51.1;71.4) for nivolumab alone or in combination, respectively. We showed that metastatic melanoma patients, treated with the combination or nivolumab alone who were alive and had not progressed by the five-year time-point, can be considered as functionally cured. The robust statistical approach proposed could be applied to other clinical settings when the plausibility of cure is to be validated.
Colostrum feeding is essential for calf immunity, nutrition, and neonatal survival. To ensure availability when maternal supply is insufficient, various storage and preservation methods have been adopted in dairy management. The objective of this study was to investigate the impact of different colostrum processing methods on metabolic and endocrine parameters in newborn calves. Eighteen calves (15 Holstein, 3 Holstein x Limousin crossbreds) were separated from their dams immediately after birth and assigned to one of 3 groups. Calves were fed 2.5 L of either pooled unprocessed colostrum (UPC), pooled heat-treated colostrum (HTC), or vacuum-dried colostrum (VDC) produced from the same unprocessed colostrum batch at 4 h and 12 h postpartum (p.p.). On d 2 and 3 p.p., animals received transition milk (bulk tank milk mixed with 10% of the respective colostrum source), and from d 4 onwards bulk tank milk twice daily. Blood samples were collected at 4, 12, and 24 h p.p., and thereafter once daily until d 7 p.p. before morning feeding. Metabolic and endocrine parameters including total protein (TP), IgG, aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), glucose, insulin, cortisol, glucagon, nonesterified fatty acids (NEFA), triglycerides (TG), and total cholesterol (TC) were analyzed. Total protein and IgG concentrations were greater in HTC and VDC until d 2 compared with UPC. Activity of GGT at 12 h p.p. was greater in HTC and VDC compared with UPC. Insulin concentrations did not change in HTC (P = 0.31) and VDC (P = 0.99) until d 2, whereas a decline was observed in UPC after 12 h p.p. (P < 0.05). Glucagon concentrations were greater in HTC and VDC up to d 2 compared with UPC. Cortisol concentrations decreased in all groups until 24 h p.p. Colostrum processing did not affect lipid metabolism related parameters, including NEFA, TG, and TC. Our results demonstrate that heat treatment and vacuum-drying of colostrum were associated with differences in circulating IgG, metabolic, and endocrine parameters in neonatal calves, suggesting potential effects on postnatal metabolic adaptation.
Intrapleural tissue plasminogen activator (tPA) and DNase are used when drainage of loculated pleural effusions is inadequate, but the real-world performance of pragmatic once-daily protocols remains uncertain. We performed a retrospective cohort study across seven hospitals between January 1, 2019, and December 31, 2020. Adults who received intrapleural tPA 20 or 50 mg once daily with optional DNase 5 mg once daily for complicated pleural effusion, empyema, or hemothorax were included. The primary outcome was treatment success, defined as survival to hospital discharge without surgical intervention during the index admission. Secondary outcomes included chest tube drainage change, hospital length of stay, ICU length of stay, mortality, major bleeding, and peri-procedural pain requiring analgesics. A post hoc subgroup analysis compared monotherapy with combination therapy. Among 120 included patients, treatment success occurred in 102 (85.0%; 95% CI, 77.3%-90.9%). The median paired increase in chest tube drainage was 487.5 mL (IQR, 72.5-979.0; P < .001). Major bleeding occurred in one patient (0.8%), whereas peri-procedural pain requiring additional analgesia occurred in 69 (57.5%). In the exploratory subgroup analysis, treatment success was 83.8% with tPA monotherapy and 87.0% with tPA/DNase combination therapy. In this multicenter real-world cohort, standardized intrapleural tPA with or without DNase was associated with high observed treatment success, substantial increases in drainage, and rare major bleeding. Comparative findings between combination therapy and monotherapy should be interpreted cautiously because treatment allocation was nonrandomized and exposure groups were imbalanced.
The study aimed to investigate the potential protective effects of camel milk against aspirin-induced gastric mucosal injury. The role of camel milk therapy in improving health status in rabbits was investigated through diagnostic and histological examinations of gastric tissues. All rabbits, 32 New Zealand white rabbits weighing between 1200 and 1800 g and aged between 3 and 5 months, were housed in standard laboratory environments (60% humidity, 20°C-25°C, and typical field rearing), and the animals were randomly divided into four groups, each containing eight rabbits. The control Group S represented the control group, while Group S1 received camel milk (15 mL/day) orally once daily. The Group S2 received a dose of 150 mg/kg body weight (BW) of the drug aspirin once daily oral dose. Whereas the Group S3 received a 15 mL/day dose of camel milk, Group S3 received camel milk 15 mL/day together with aspirin 150 mg/kg BW/day. The drug aspirin was administered once daily. The experiment lasted for a period of 70 days in a controlled environmental laboratory after performing a histopathological examination of the stomach tissues, as well as a biochemical analysis of liver function markers. The incidence and severity of gastric ulcers were significantly reduced in the camel milk-treated group compared to the aspirin group (p < 0.05). In addition, the significant differences (p < 0.01) in liver function were observed in variation in ALT, DB, TP, albumin, and ALP in Group S1 in comparison to Group S. The results show a nonsignificant decrease in AST and TB levels in both Groups S1 and S3, compared to Group S. The histological results also showed a decrease in inflammatory infiltration and tissue damage in the rabbit Group S3 compared to the Group S2 that consumed aspirin only. In conclusion, the results showed that one of the properties of camel milk, antioxidant and anti-inflammatory activity, is highly effective in preventing and treating aspirin-induced gastric and liver damage.
Chemotherapy-induced neutropenia (CIN) and its severe complication, febrile neutropenia, remain major challenges in oncology. Although granulocyte colony-stimulating factors (GCSFs) have reduced the incidence of these complications, limitations related to dosing schedules, polyethylene glycol (PEG)-associated concerns, and pharmacokinetic variability persist. Efbemalenograstim alfa (F-627) is a novel non-PEGylated Fc-fusion G-CSF designed for once-per-cycle administration. This systematic review and meta-analysis evaluated the efficacy and safety of efbemalenograstim alfa compared with placebo or standard G-CSFs in patients at risk of chemotherapy-induced neutropenia. A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42024628001). MEDLINE, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to 22 October 2025. Randomized controlled trials evaluating efbemalenograstim alfa in patients receiving myelotoxic chemotherapy were included. Efficacy outcomes included duration of severe neutropenia (DSN), incidence of severe neutropenia (ISN), and depth of absolute neutrophil count (ANC) nadir. Safety outcomes included adverse events, serious adverse events, and treatment discontinuations. Random-effects meta-analyses were performed. Five randomized controlled trials involving approximately 800 patients with breast cancer receiving myelotoxic chemotherapy were included. Compared with placebo or standard GCSFs, efbemalenograstim alfa demonstrated comparable efficacy in reducing DSN during the first chemotherapy cycle (MD -0.32 days; 95% CI -0.79 to 0.14) and ISN (RR 0.86; 95% CI 0.73-1.03). A significant improvement in ANC nadir was observed (MD +0.40 ×10⁹/L; p = 0.0002). Rates of serious adverse events (RR 0.71; 95% CI 0.29-1.70), adverse events, and treatment discontinuations were comparable between groups. Heterogeneity was primarily attributable to the inclusion of a placebo-controlled study. Efbemalenograstim alfa demonstrated efficacy and safety comparable to currently available long-acting G-CSFs for the prevention of chemotherapy-induced neutropenia. Its Fc-fusion structure enables once-per-cycle administration without PEGylation, supporting its potential as an alternative long-acting G-CSF. Further studies are needed to evaluate long-term outcomes and real-world effectiveness.
Lysosomal disorders (LDs) are a heterogeneous group of rare inherited disorders characterized by multi-system involvement and high comorbidity burden, which raises concerns about severe COVID-19 outcomes. Conversely, because SARS-CoV-2 relies on endolysosomal pathways for cellular entry and replication, certain LDs may exert a protective effect against viral pathogenesis. Prior clinical evidence investigating LDs and severe SARS-CoV-2 infection has been limited by small sample sizes and inconsistent findings. Therefore, to resolve these conflicting biological hypotheses and estimate population-level outcomes, we conducted a large-scale retrospective cohort study using nationwide U.S. harmonized electronic health record data from the National Clinical Cohort Collaborative (N3C). This design utilized longitudinal records starting January 1, 2018, to evaluate COVID-19 infections captured between January 1, 2020, and July 11, 2024. The study included 16,380 individuals, comprising 5,460 patients with lysosomal disorders and 10,920 matched controls. Patients with LDs had significantly higher odds of COVID-19 hospitalization compared with controls (OR = 1.86, 95% CI: 1.70-2.04). Elevated odds were observed across the evaluated categories, but varied substantially. Notably, neurodegenerative LDs such as neuronal ceroid lipofuscinosis (OR = 9.32) and metachromatic leukodystrophy (OR = 2.33) remained associated with hospitalization after adjustment for comorbidities. Contrarily, the elevated odds for Fabry disease and Gaucher disease were no longer significant after adjustment. Mortality among hospitalized patients with LDs was comparable to that of matched controls (one-year survival: 82.1% vs 82.0%), suggesting that LD status does not independently worsen survival once hospitalization occurs. Patients with LDs were at an increased odds of COVID-19 hospitalization, driven by a combination of elevated comorbidity burden and disorder-specific effects, which vary significantly across LD categories. This study clarifies that excess risk is concentrated in the transition to hospitalization. These patients may thus require personalized clinical care to mitigate the negative consequences of COVID-19.
To assess weight loss with atogepant 60 mg once daily during long-term treatment of chronic migraine (CM) and episodic migraine (EM) among participants previously failed by two to four classes of conventional oral preventive medications. The risk of migraine, including CM, in individuals with obesity is higher than in those without obesity. Calcitonin gene-related peptide has been linked to the pathophysiology of both obesity and migraine. Weight loss with atogepant, a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of migraine, has been observed during the 12-week EM and CM trials, as well as in long-term (40- or 52-week) EM trials. Long-term effects of atogepant on body weight in participants with increased migraine burden (i.e., EM or CM) have not been reported. In this interim analysis of a safety endpoint from study 312, a phase 3, open-label, extension study, weight loss was assessed in the overall population and by prior participation in each lead-in study (12-week double-blind treatment period): PROGRESS (phase 3, multicenter, randomized, controlled study in CM) or ELEVATE (phase 3, multicenter, randomized, controlled study in EM treatment failure). Change from baseline in body weight at each study visit through end of treatment (PROGRESS and ELEVATE) or up to week 52 (study 312) was assessed (safety endpoint). Proportions of participants with ≥5% weight loss at any time, at the end of the lead-in study, or at week 52 in study 312 were evaluated. Participants from PROGRESS (n = 325) and ELEVATE (n = 270) rolled over to study 312 (n = 595) and were treated with atogepant 60 mg once daily. In study 312, mean (standard deviation) body weight decreased over time (-2.16 kg [5.89 kg; -4.76 lb] at week 52), with 44.8% (265/592) of participants experiencing a ≥5% weight loss at any time during the study and 29.5% (140/474) experiencing a ≥5% weight loss at week 52. In study 312, weight loss from lead-in study baseline was evident as early as week 4 and appeared to plateau around weeks 28 to 36, reaching a maximum numerical weight loss at week 44. Higher baseline body mass index was associated with greater odds of achieving ≥5% weight loss both at any time and at week 52. No significant effect of sex, race, adverse drug reactions, or therapeutic response to treatment was observed. Participants receiving atogepant 60 mg once daily for long-term preventive treatment of migraine were observed to have a decrease in mean body weight after 1 year of open-label treatment. Approximately 30% of participants experienced a clinically meaningful (≥5%) weight loss threshold after 1 year of open-label treatment. Future studies are needed to further characterize the mechanisms of weight loss associated with atogepant treatment. In this study, we evaluated change in body weight over at least 52 weeks of treatment with atogepant 60 mg for the preventive treatment of migraine. Consistent with previous findings from short‐term studies in episodic or chronic migraine and longer‐term studies in episodic migraine, we found that nearly half of atogepant‐treated participants experienced at least 5% weight loss at any point. Individuals with higher baseline body mass index were more likely to experience clinically meaningful (≥5%) longer‐term weight loss.
Icotrokinra, a targeted oral peptide, precisely blocks the interleukin-23 receptor. In two phase 3 moderate-to-severe plaque psoriasis trials, ICONIC-ADVANCE 1 (NCT06143878) and ICONIC-ADVANCE 2 (NCT06220604), icotrokinra provided significantly higher skin clearance rates versus placebo at Week 16 and deucravacitinib at Week 16 and 24. Report findings through Week 52 of ICONIC-ADVANCE 1&2. ICONIC-ADVANCE 1&2 randomised (2:1:2/4:1:4) adults with moderate-to-severe plaque psoriasis (body surface area ≥10%, Psoriasis Area and Severity Index [PASI] ≥12, Investigator's Global Assessment [IGA] ≥3) to icotrokinra 200 mg, placebo (transition to icotrokinra at Week 16), or deucravacitinib 6 mg once daily (transition to icotrokinra at Week 24). Outcomes assessed through Week 52 included proportions of participants achieving IGA 0/1 (with ≥2-grade improvement from baseline), PASI 90, IGA 0, PASI 100, scalp-specific IGA (ss-IGA) 0/1, patient-reported outcomes (clinically meaningful improvement [CMI; ≥4-point reduction] in Psoriasis Symptoms and Signs Diary [PSSD] itch, PSSD symptom score 0, Dermatology Life Quality Index [DLQI] 0/1), and adverse events (AEs). ICONIC-ADVANCE 1&2 randomised 1505 participants (774/731). Across the studies, skin clearance rates among icotrokinra-randomised participants increased through Week 24 and were durable through Week 52, with ∼70%-75% exhibiting clear/almost clear skin (IGA 0/1, PASI 90) and ∼50% demonstrating completely clear skin (IGA 0, PASI 100) during Weeks 24-52. Among participants achieving clear/almost clear skin at Week 16, ∼85%-90% maintained response at Week 52. Response rates for ss-IGA 0/1 and patient-reported outcomes were also durable through Week 52. Participants who transitioned from placebo or deucravacitinib to icotrokinra exhibited increasing response rates that were comparable to icotrokinra-randomised participants through Week 52. The AE profile of icotrokinra was similar to placebo through Week 16 and showed lower AE rates than deucravacitinib through Week 24; no safety signals were observed through Week 52. Once-daily icotrokinra provided robust, durable skin clearance and symptom improvement, with no safety signals, through Week 52 in adults with moderate-to-severe plaque psoriasis. Participants transitioning from placebo or deucravacitinib to icotrokinra achieved similar increased response rates to icotrokinra-randomised participants through Week 52. Findings support icotrokinra as a systemic therapy with long-term robust disease control and a favourable safety profile.
The combination of doravirine and islatravir (DOR/ISL) is a novel two-drug regimen for HIV-1. Early development faced challenges due to dose-dependent immunological signals. We aimed to synthesize the evidence on the efficacy and safety of DOR/ISL across all treatment-experience categories, specifically evaluating the impact of islatravir dosage (0.25 mg vs 0.75 mg) on clinical and immunological outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following PRISMA guidelines. We searched PubMed, Embase, Cochrane Library, and Google Scholar from inception through April 2026. Primary outcomes were virological suppression (<50 copies/mL) and mean change in CD4+ T-cell count at week 48. Data were pooled using random-effects models. Islatravir dose was evaluated as a pre-specified moderator. Quality was assessed using Cochrane RoB 2.0 and certainty of evidence was graded using the GRADE approach. Seven RCTs (n = 3,600 participants) were included. At Week 48, DOR/ISL showed non-inferior suppression rates (RR 1.01 [95% CI 0.99-1.02]; p = 0.516; moderate-certainty evidence) and a statistically significant reduction in virological failure risk (RR 0.55 [0.33-0.92]; p = 0.022) compared to active control. Overall CD4+ gain was lower with DOR/ISL (MD -34.55 cells/μL; low-certainty evidence); however, a profound moderator effect of dose was observed (p < 0.0001). The 0.75 mg dose was associated with significant CD4+ and lymphocyte declines, whereas the approved 0.25 mg dose was immunologically neutral. DOR/ISL was weight-neutral compared to bictegravir/emtricitabine/tenofovir alafenamide (MD -0.25 kg [-0.66 to 0.16]; low-certainty evidence). DOR/ISL 100/0.25 mg once daily achieved virological suppression comparable to standard-of-care ART regimens and was associated with lower rates of virological failure compared with active comparators. The immunological safety concerns observed in early trials were successfully resolved by dose optimization. These findings support the use of DOR/ISL (IDVYNSO) as a potential treatment option for both treatment-naïve and virologically suppressed adults while emphasizing long-term safety surveillance.
The impacts of open-pit mining-induced mineral dust deposition on the accumulation of rare earth elements (REEs) in residential indoor dust and the associated health risks remain poorly understood. Here, indoor dust samples were collected from residential areas within and beyond the Bayan Obo mining region. By integrating chemical analyses with mineral dust deposition simulated using the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem), we investigated the spatial patterns, controlling factors, and health implications of REEs in indoor dust. The open-pit mining area acted as a persistent source of mineral dust emissions throughout the year, with pronounced seasonal variability in dust flux (0.133-49.2 t km-2; mean 7.71 t km-2). Light REEs (LREEs) showed pronounced enrichment and clear distance-decay gradients relative to heavy REEs (HREEs), with concentrations decreasing progressively away from the mine. Spatial statistical analyses revealed strong positive associations between mineral dust deposition and LREE enrichment, with high-high clusters concentrated within approximately 40 km of the mine. Bayesian regression demonstrated a consistently positive and statistically robust influence of dust deposition on REEs, with substantially stronger effects on LREEs. Shapley Additive exPlanations (SHAP) analysis further indicated a nonlinear response, whereby REE accumulation became markedly enhanced once dust deposition exceeded a threshold. Health risk assessment showed that non-carcinogenic risks were dominated by LREE exposure, particularly for children, and that mining-related sources contributed over 70% of non-carcinogenic risk. Overall, this study establishes a process-based linkage between open-pit mining, atmospheric dust deposition, indoor contamination, and human health risk. These findings provide critical insights for addressing similar environmental and health challenges in other mining regions.
Antibiotic heteroresistance is a form of within-isolate susceptibility heterogeneity in which an apparently susceptible bacterial population contains rare subpopulations capable of growth at substantially higher antibiotic concentrations. It is commonly defined as resistant minorities occurring at frequencies ≥10-7 and growing at concentrations at least eight-fold above those that inhibit the dominant population, as demonstrated by population analysis profiling or related assays. This phenomenon has been described in diverse Gram-negative and Gram-positive pathogens and across multiple drug classes and is frequently characterized by instability, with resistant subpopulations expanding under treatment and contracting once drug pressure is relieved. This dynamic behavior contributes to systematic under-detection by routine antimicrobial susceptibility testing, which is optimized for population-average endpoints and may miss clinically relevant resistant tails, helping explain treatment failure despite 'susceptible' results. Mechanistically, heteroresistance spans a continuum from genotypic processes, including gene amplification, plasmid copy-number variation, transposition, and point mutations, to phenotypic mechanisms driven by reversible regulatory and physiological states such as transcriptional reprogramming, stochastic expression variability, and intergenerational phenotypic memory. These mechanisms can coexist and shift under antibiotic selection, supporting the view that heteroresistance may act as an evolutionary intermediate linking susceptibility and stable resistance. Recent advances in single-cell phenotyping, copy-number-aware genomics, transcriptomics, pharmacodynamic and population modeling, and machine-learning-assisted diagnostics offer new opportunities to detect and interpret susceptibility distributions. Integrating these approaches into clinical microbiology and stewardship will be essential to improve risk stratification, guide therapy, and predict resistance evolution.
Low molecular weight heparin (LMWH) remains a widely utilized parenteral anticoagulant in hospital and outpatient settings for thromboprophylaxis and treatment of venous thromboembolism. While LMWH typically does not require routine monitoring due to predictable pharmacokinetics, anti-factor Xa (anti-Xa) monitoring is indicated in specific populations, including those with renal impairment, extremes of body weight, pregnancy, or unexplained treatment failure. LMWH monitoring relies exclusively on chromogenic anti-Xa assays, as LMWH's predominant anti-Xa activity with minimal anti-IIa effect renders activated partial thromboplastin time insensitive. Therapeutic targets are context-dependent: peak anti-Xa levels of 0.5 to 1.2 U/mL for twice-daily therapeutic dosing or 1.0 to 2.0 U/mL for once-daily dosing, measured 3- to 5-hour postdose. We report external quality assessment findings for anti-Xa testing of LMWH from the past 6 years (2020-2025 inclusive) using RCPAQAP (Royal College of Pathologists of Australasia Quality Assurance Program) data, an international program with approximately 150 laboratory enrolments. Four samples are assessed annually at varied LMWH concentrations (0, 0.2-0.3, 0.5-0.6, 0.8-1.0 U/mL). Good reproducibility was demonstrated for duplicate samples across surveys. Coefficient of variation data revealed moderate variability (10-25%) for detectable LMWH levels, lower than unfractionated heparin (UFH) monitoring variability. Method-related differences were observed, with Siemens Innovance anti-Xa assays yielding slightly higher values than Werfen HemosIL or Stago STA assays. Participant interpretations of LMWH levels (below/within/above therapeutic range) showed greater variability than UFH due to multiple valid therapeutic ranges for LMWH depending on dosing context. Overall, laboratories demonstrated acceptable analytical and interpretative performance for LMWH monitoring, which should provide some reassurance to both patients and their clinical carers.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intensely pruritic episodes and eczematous lesions. This disease is prevalent in up to 25% of children, with about half of these cases persisting into adulthood. This systematic review aims to examine two new topical therapies for AD, roflumilast and tapinarof, and investigate the adverse events  associated with their use. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and registered in PROSPERO (CRD420251066719). A search was performed in Scopus, Embase, PubMed, Cochrane Library, and Web of Science on 2 June 2025. Randomized controlled trials were included if they reported adverse event outcomes in pediatric patients with AD after either roflumilast or tapinarof treatment; studies with mixed pediatric and adult patients were eligible for inclusion. Studies were excluded if they lacked roflumilast or tapinarof treatment, did not include pediatric patients with AD, or did not report adverse event outcomes. Risk of bias was assessed using the Cochrane Risk of Bias tool. Adverse events were reported as occurrence (n) and frequency (n/N, %) within pooled studies for the roflumilast and tapinarof groups. Risk ratios (RR) and 95% confidence intervals (CI) comparing treatment with vehicle control were calculated using the Mantel-Haenszel fixed-effect model. Seven studies with a total of 3615 patients with AD using roflumilast (N = 1979), tapinarof (N = 658), or vehicle control (N = 978) were included in the final data extraction and analysis. Analyses included adverse event outcomes for mixed pediatric and adult patients. Three studies assessed once-daily 0.05% or 0.15% roflumilast cream use in patients with a mean age of 19.8 years. Four studies assessed once-daily 0.5% or 1% tapinarof cream use in patients with a mean age of 8.15 years. Both therapies displayed significant risks of treatment-emergent adverse events (TEAE) compared with vehicle controls (roflumilast: RR = 1.46, 95% CI = [1.20-1.77] with p = 0.0001; tapinarof: RR = 1.49, 95% CI = [1.24-1.79], p < 0.0001). Treatment-related TEAEs were significantly increased with roflumilast use (RR = 1.92, 95% CI = [1.15-3.19], p = 0.01), but not tapinarof use (RR = 1.30, 95% CI = [0.89-1.91], p = 0.17). Roflumilast was associated with nondermatologic adverse events, while tapinarof was found to have an association with dermatologic adverse events. Some limitations include the lack of direct comparative studies, limited data in pediatric and young adult populations, and heterogeneity of reported adverse events. Despite this, roflumilast and tapinarof demonstrate distinct adverse event profiles. Roflumilast was associated with an increased risk of treatment-related and nondermatologic adverse events, while tapinarof was associated with dermatologic adverse events. These findings highlight the importance of individualized treatment selection and careful monitoring of adverse events  when incorporating these therapies into the management of atopic dermatitis.
This randomized, placebo-controlled clinical trial evaluated the clinical and biological effects of laser-assisted therapy on the healing of soft tissue at the pontic site prior to fixed partial denture rehabilitation. A total of 45 patients requiring a single-tooth extraction, followed by a three-unit fixed partial denture rehabilitation, were randomly allocated to one of three groups (n = 15 in each group). Gallium-Aluminum-Arsenide (GaAlAs) diode laser (GRR laser), Neodymium-doped Yttrium Aluminium Garnet laser (Nd: YAG) and placebo. Laser applications were performed once daily for five consecutive days following tooth extraction. Clinical healing was assessed using wound dimension measurements and the healing index (HI) at baseline, day 7, and day 14. Postoperative pain was evaluated using visual analog scale (VAS) scores recorded daily from postoperative day 1 to day 7. Gingival crevicular fluid (GCF) samples were collected at the same time points and analysed for transforming growth factor beta 2 (TGF-β2) levels using an enzyme-linked immunosorbent assay. Intergroup and intragroup comparisons were performed using the appropriate statistical tests (α = 0.05). No significant differences were observed among groups at baseline for any evaluated parameter (p > 0.05). At day 7 and day 14, significant intergroup differences were detected for wound dimensions, clinical healing index scores, VAS pain scores, and GCF TGF-β2 levels (p < 0.001). The GRR laser group demonstrated significantly greater wound size reduction, higher clinical healing index scores, lower postoperative pain levels, and higher TGF-β2 concentrations compared with the Nd: YAG laser and placebo groups. Nd: YAG laser group showed improved outcomes compared with placebo, although these differences were less significant than those observed in the GRR group. Laser-assisted therapy accelerated the healing of soft tissue at the pontic site prior to fixed partial denture rehabilitation. The GRR laser protocol achieved superior clinical and biological outcomes compared to the Nd: YAG laser and the placebo. These results suggest that optimised low-level laser therapy (LLLT) could be a valuable additional treatment for accelerating pontic site maturation and making the prosthetic workflow more predictable. NCT07415434, Retrospectively registered (09.02.2026).
In 2018, Uganda adopted Dolutegravir (DTG)-based regimens as the preferred first-line antiretroviral therapy (ART). This qualitative study explored the perspectives of people living with HIV (PLHIV) regarding switching from stable ART regimens to DTG at the Joint Clinical Research Centre (JCRC). We purposively sampled 24 participants (16 DTG-experienced, 8 DTG-naïve) and conducted face-to-face in-depth interviews. Data were analysed using inductive thematic analysis. DTG-experienced participants were those switched to DTG from a previous stable regimen, while DTG-naïve participants were eligible for but had not yet switched. Key themes emerged: (1) Initial apprehension due to fear of side effects, feeling stable on previous regimens, and perceiving the switch as compulsory or rushed; (2) Appreciation for DTG's benefits (e.g., smaller pill size, once-daily dosing, rapid viral suppression) which mitigated initial hesitancy over time; (3) The critical role of communication and preparation in facilitating a positive transition experience. The findings indicate that while switching from stable treatment initially creates tension, hesitancy decreases as benefits are realized and concerns are addressed through continuous, supportive health education. Effective client-provider communication is essential for successful ART policy transitions.
Energetic electrons in Earth's inner radiation belt pose significant hazards to spacecraft systems, with the strongest radiation in low-Earth orbit (LEO) mostly confined to the South Atlantic Anomaly (SAA) region. Once considered stable, the inner belt is now understood to exhibit significant variability. Using data from the low-Earth-orbit Macau Science Satellite-1 mission, we report transient distortions of the SAA radiation environments, observationally characterized by enhanced fluxes of energetic electrons outside the traditional SAA radiation region, appearing either attached to or detached from its boundary. We show that these distortions can be explained by large-scale electric-field perturbations that adiabatically alter the electron mirror heights, which can be further modulated by ultra-low-frequency waves. Test-particle simulations successfully reproduce the observational features and provide crucial constraints on properties of the associated electric fields. These findings reveal a distinct manifestation of inner-belt variability, extending the electron radiation risks beyond the expected boundaries of the SAA radiation environments.
Little is known about the content of routine smoking cessation support in primary care and how it relates to abstinence. While 121 behavior change techniques (BCTs) have been identified for cessation treatment, English treatment guidelines recommend 30 across cessation consultations. We sought to identify: (1) BCTs delivered during routine cessation support in primary care in England; (2) associations between abstinence and (a) the total number of BCTs used, (b) delivery of the 30 recommended BCTs, (c) delivery of individual BCTs. In an evaluation trial across 32 English General Practices, 149 pre-quit consultations (across 29 practitioners trained in cessation support) from a multisession cessation program were audio-recorded, transcribed, and analyzed for BCT delivery using a modified BCT taxonomy v1 and smoking-specific taxonomy. Abstinence was collected at 4-weeks (biochemically verified), 8-weeks (primary outcome, self-reported), and 6-months (self-reported) post quit date. Multilevel modelling assessed associations. Of 121 BCTs, 85 were delivered in at least one consultation. A mean of 13.4 (SD = 2.76) of recommended BCTs were delivered, with 33% (10/30) delivered in at least half of the consultations. Total BCTs delivered were not associated with abstinence. Delivery of more guideline-recommended BCTs was only associated with abstinence at 4 weeks (OR = 1.03, 95% CI 1.00-1.06; P = .03). One BCT was positively associated, and one negatively associated with abstinence. One-third of recommended BCTs were delivered in at least 50% of initial consultations, with delivery associated with short-term abstinence. Limited practitioner time may constrain BCT delivery and is a consideration for future guidelines. The Clinical Trials Registration #ISRCTN 56702353. Stop smoking support is regularly provided in primary care. However, it is not clear what this support includes (e.g. which behavior change techniques [BCTs]), how well this follows recommended guidelines, and whether the included content actually leads to people quitting. There are 121 known BCTs that can support quitting, but guidelines suggest using 30 key BCTs. We analyzed 149 recorded conversations between patients and primary care health professionals before their planned quit date, checking which BCTs were used and if they were linked to quitting success. We found that 85 different BCTs were used at least once, but on average, 13 of the recommended 30 were used. Overall, using more BCTs did not link to better quit outcomes. However, using more of the recommended BCTs was linked to quitting success at 4-weeks, but not at 8-weeks or 6-months. Only one specific BCT helped, while another seemed to hinder success. This suggests that short-term quitting may benefit from using more guideline-recommended BCTs, but time limits in appointments may prevent full use. Future guidelines may need to account for this challenge.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
Urban venues serve as arenas for social mixing, yet less is known about how public transit infrastructure shapes the geography of mixing at specific locations. This study examines how transit catchment diversity-the socioeconomic heterogeneity of populations reachable by public transit-associates with visitor diversity at points of interest (POIs) in nine Swedish and three US cities. Using mobile phone GPS traces and aggregated foot traffic data from 2024, we compute visitor diversity indices based on visitors' home-neighborhood birth-background composition and employ spatial regression models and geographically weighted regression (GWR). Transit catchment diversity positively predicts visitor diversity across nearly all cities, but this association is robust only in the largest metropolitan areas; in smaller cities, the coefficient attenuates to insignificance once geographic catchment composition, centrality, and venue density are controlled. Spatial spillovers in visitor diversity follow general geographic proximity rather than shared transit-stop connectivity, suggesting that the association operates through catchment population composition rather than station-level linkages. Transit-diversity hotspots occur not in already-diverse venues, but in lower-diversity POIs with lower commercial density, greater distance from transit in US cities, and greater centrality in Sweden. These patterns are consistent with transit-accessible population composition being associated with visitor diversity, particularly where alternative pathways to diverse co-presence are limited.
Healthcare systems' growing complexity has driven the adoption of design thinking (DT) pedagogies to cultivate creativity, collaboration, and adaptive expertise among nursing graduates. Faculty teaching behaviours play a critical role in how DT curricula are enacted, yet it remains unclear whether skill-based DT competencies or trait-based dispositions are more strongly associated with DT-aligned teaching behaviours. This study examined their relative and indirect associations among interdisciplinary faculty involved in DT-integrated nursing education in Taiwan. A cross-sectional survey was conducted with 95 faculty members from 12 Taiwanese institutions offering DT-integrated nursing courses. Measures included the 14-item Creative Teaching Behaviours Scale (CTBS) as a proxy for DT-aligned teaching behaviours, the 18-item Creative Synthesis Inventory-Taiwan version (CSI-TW) for skill-based DT competencies, and the 9-item Design Thinking Traits Questionnaire-Taiwan version (DTTQ-TW) for trait-based DT dispositions. Analyses included exploratory group comparisons, hierarchical multiple regression, and mediation analysis, controlling for demographic characteristics and DT-related teaching experience. Faculty with higher CTBS scores demonstrated significantly higher levels of both skill-based and trait-based DT competencies at the descriptive level. Hierarchical regression analysis showed that skill-based DT competencies (β = 0.429, p < 0.05) and DT teaching experience (β = 0.379, p < 0.05) were independently associated with DT-aligned teaching behaviours, explaining 27.2% of the variance. Trait-based DT dispositions did not contribute additional explanatory value once skills were taken into account (ΔR² = 0.001, p = 0.784). Mediation analysis further suggested an indirect association, whereby trait-based DT competencies were related to teaching behaviours through skill-based competencies, with no detectable direct association. Within this cross-sectional sample, DT-aligned teaching behaviours were more closely associated with skill-based DT competencies and accumulated teaching experience than with trait-based dispositions. The findings are consistent with a distal-proximal interpretation derived from social cognitive theory and suggest that faculty development initiatives should prioritise sustained, hands-on training in DT process skills and authentic teaching practice opportunities rather than trait-based selection.